Cytokinins can be chemically characterised as N6-substituted derivatives of adenine. The current nomenclature based on the system suggested by Letham (Planta 181: 361-364, 1974) and Letham and Palni (Ann. Rev. Plant. Physiol. 34: 163-197, 1983) was originally suggested for zeatin (Z) and isopentenyladenine (iP). Conjugation of purine ring is labelled by number of substituent position, as shown in the overview for iP.
In the overview of chemical formulas of fundamental cytokinin bases have the following meaning: iP—N6-(Δ2-isopentenyl)adenine, Z—trans-zeatin, DHZ—dihydrozeatin, BAP—6-benzylaminopurine, oT—ortho-topolin, mT—meta-topolin.
Based on their side chain structure, cytokinins can be divided into two groups: isoprenoid and aromatic. Isoprenoid cytokinins are represented by compounds derived from the following bases: N6-(Δ2-isopentenyl)adenine, dihydrozeatin and zeatin. 6-benzylaminopurine, meta- and ortho-topolin and their metabolites belong to the aromatic cytokinin group.
In case of isoprenoid cytokinins, conjugation plays an important role, including modifications of purine ring and N6-side chain. The major cytokinin conjugates in plants are 9-ribosides, 9-ribotides, 3-, 7-, 9-a O-glukosides, O-xylosides, 9-ribosylglukosides, O-acetyl a O-allyl derivatives and also alanin conjugates (the details see in Mok, D. W. S., Mok, M. C.: Cytokinins: Chemistry, Activity and Function. CRC Press, Boca Raton, London, Tokyo 1994).
Whereas free bases represent an active cytokinin form, (Laloue and Pethe, In: Wareing, P. F. (ed.): Plant Growth Substances 1982. Pp. 185-195. Academic Press, London 1982), their ribosides are an important xylem transport forms and dominant forms in plant tissues. Riboside-5′-monophosfates are central compounds in cytokinin metabolism (Laloue et al. FEBS Let 46: 45-50, 1974; Physiol. Veg. 13: 781-796, 1975; Plant Physiol. 59: 478-483, 1977; In: Guern, J., Péaud-Lenoël, C., (eds.): Metabolism and Molecular Activities of Cytokinins. Pp. 80-96. Springer-Verlag, Berlin 1981; Mok et al., J. Plant Physiol. 130: 423-431, 1987), which are accumulated in plant cells even against high concentration gradient, because of cell membrane impermeability for these metabolites (Laloue et al., 1974, 1975, Laloue and Pethe In: Wareing, P. F. (ed.): Plant Growth Substances 1982. Pp. 185-195. Academic Press, London 1982.).
Cytokinins play an important role in many different developmental processes, including cell division, growth and differentiation, as well as flower and fruit development. They can break seed dormancy, inhibit apical dominance and stimulate the growth of side shoots, delay the cell aging, increase stress resistance, affect membrane permeability and cause accumulation of various metabolites in the site of their application (Letham a Palni 1983—Ann. Rev. Plant. Physiol. 34: 163-197, 1983, Mok, D. W. S., Mok, M. C.: Cytokinins: Chemistry, Activity and Function. CRC Press, Boca Raton, London, Tokyo 1994).
Since all living organisms on the Earth have been evolutionary developing together for many million years, the presence of regulatory interactions of plant compounds, as cytokinins are, in animals and human can be assumed. Cytokinin-derived compounds probably affect many different molecular mechanisms in animal and human cells. We have recently discovered that novel generations of anti-inflammatory, anticancer, immunosuppressive, antiviral and other drugs could be based on N6-substituted purines and their derivatives.
It is an object of this invention to provide anticancer, immunosuppressive, growth-regulatory, morphogeneticaly active and antisenescence heterocyclic compounds derived from C2- and phenyl-substituted 6-benzylaminopurine ribosides having improved selectivity and efficiency index, i.e. which are less toxic yet more efficacious than analogues known heretofore.